David I. Sandberg, MD, FAANS, FACS, FAAP, Professor and Director, Division of Pediatric Neurosurgery and Dr. Marnie Rose Professorship in Pediatric Neurosurgery, McGovern Medical School at UT Health, talks about a new chemotherapy treatment for brain cancer, injected directly into the brain.
Interview conducted by Ivanhoe Broadcast News in November 2017.
What kind of cancers are you studying with this technique, injecting chemotherapy into the brain, what cancers are you studying?
Dr. Sandberg: We’re studying malignant brain tumors that occur in children in a specific region of the brain. Specifically this is the back of the brain which is called the posterior fossa and there are tumors that are currently treated by radiation, surgery and chemotherapy. And the primary tumors that we treat are medulloblastoma, ependymoma and atypical teratoid/rhabdioid tumor.
How common are these, are these some of the most common cancer?
Dr. Sandberg: There are roughly four thousand new brain tumors in the United States in children each year. And medulloblastoma is the most common of these; so there are probably about a thousand new cases per year of medulloblastoma comprises twenty five percent of that group.
What’s a typical prognosis for these patients?
Dr. Sandberg: These tumors used to be a death sentence but the treatments have changed and improved dramatically and so the current survival for some of these tumors is much better than it used to be. The problem is that when the tumors recur, many patients do not survive because we don’t have great treatments for recurrent tumors and also the treatments that we have to offer have significant toxicity.
When you say they recur are they still localized or have they metastasized at that point?
Dr. Sandberg: Unlike typical tumors that you think about, breast cancer, prostate cancer; those tumors kill you by spreading around your body and going to different organs right. These tumors don’t do that, they don’t tend to go to other organs they recur either locally in the brain or they occur in the spaces where the fluid circulates in the brain and the spine, so they stay confined to the central nervous system. And that’s very important because that’s the rational for my treatment approach which is different from what’s normally given.
If they don’t spread why are the recurrences harder to treat than initial cancer?
Dr. Sandberg: The recurrences are harder to treat because when they recur often they’re not surgically resectable, the patients have already received radiation therapy and the available chemotherapy medicines we have are both inadequate and have significant side effects.
What are you studying here?
Dr. Sandberg: The standard treatment for these malignant brain tumors, there are three things that we can offer. One is surgical resection and we perform a maximal safe surgical resection of tumor. The other is radiation therapy and the third is chemotherapy. After surgery, patients with malignant brain tumors typically receive radiation therapy and chemotherapy and there are significant problems with both. Radiation therapy is very harmful to the developing nervous system and is not always effective. Chemotherapy has a problem in that when you give it into the bloodstream, into a vein; you have to get very high drug levels to try to bypass what’s called the blood brain barrier. The brain is very good at protecting itself against drugs and toxins so the problem is you have to give such high doses that some drugs don’t make it into the brain and other drugs they wreak havoc on other organs and areas, other systems in the body. And these are areas that don’t need to receive the drug because they don’t have any cancer cells. So my approach is that instead of trying to bypass the blood brain barrier with high doses of drugs that go to places where they’re not needed and cause harm, we give drugs directly into a space called the forth ventricle. And this is the first time in humans this is being done. We’re fusing drugs directly into the forth ventricle; which is the site of origin of these tumors, in the hope that we can obtain very high drug levels exactly where the tumor is. The drug that we infuse will spread around the nervous system because the fluid bases are constantly communicating with one another and avoid the systemic toxicity with standard drugs.
When you say you’re injecting it directly into the fossa, is this an IV, how is it being done?
Dr. Sandberg: You’ll see when we give our infusion today. What we do is at the time of surgery we perform a maximal safe surgical resection of the recurrent tumor and we leave a catheter which is a little tube into the fluid space of the brain called the fourth ventricle. That catheter is attached to a chamber which is called the reservoir which sits right underneath the skin in the back of the head at the bottom part of the incision. And we can very easily access that reservoir with a small needle through the skin and it’s not very painful. We can infuse drug and treat the tumor that way.
So this stays in the time during treatment and then you remove it at the end of treatment?
Dr. Sandberg: We usually tend to keep it in afterwards because it’s another surgical procedure to remove it and perhaps we it will be used later if necessary and you know it’s another operation to remove it and it’s not painful or bothersome to the patients.
What have you seen so far with the toxicity the patients experience when they’re getting this treatment as compared to high doses of systemic chemotherapy?
Dr. Sandberg: It’s night and day different. Patients who receive chemotherapy, everyone watching this knows somebody who has had cancer and they received chemotherapy, they feel sick, they feel nauseous, they’re vomiting they feel sick in so many ways. The majority of the patients and you can ask our current patient today how she feels when she gets the infusions. Their symptoms are relatively mild and some of them have no symptoms at all. That’s been the most important thing to me is we’re treating children and we don’t want them to have toxicity and watch them suffer. Of course we want to cure them of their disease, but we also want them to not feel sick. And so that’s one of the positive things of this approach.
What have you seen so far with these results, did they just start in January?
Dr. Sandberg: We started this back in 2013 with very small numbers of patients in pilot trials. This is very heavily watched by the FDA and we have to move slowly and carefully. We started with a very low dose of a very commonly used drug called Methotrexate which has been around for decades, and truthfully we thought we would probably show safety but not necessarily efficacy because we were starting with a very low dose and we wanted to be cautious because we’re infusing a drug directly into the brain and who knows what’s going to happen even though we had done seven years of safety data in animals, in pigs and nonhuman primates. To our shock all three patients in that initial pilot trial with a low dose of methotrexate had a decreased burden of their tumor compared to before the study and these kids had failed everything before that. They had failed standard surgery, radiation, standard chemotherapy approaches. Some of them had been on other clinical trials and so this is a population which had been doing badly so we were delighted with those results. But we didn’t cure anybody so our next step has been to design new trials and there will be new trials to follow these to try to maximize the outcome of these patients.
And so with the new trials there’s a combination of drugs you’re using right?
Dr. Sandberg: For this current trial that our patient you will meet today is on we are infusing two drugs. One is Methotrexate because it worked for her; she was actually one of the original patients on our trial back in 2014 and had a wonderful response. And we’ve added a second drug, Etopside, which is more commonly infused into the fluid spaces of the brain in Europe and in the United States.
What are you seeing so far with this?
Dr. Sandberg: Well we just started this trial and she’s our first patient on this new trial so we’ll see what happens. So far she’s tolerated the medicine well and we are very hopeful that we’ll enroll additional patients because these trials are hard for patients; they have to come in from out of town and they have to be in Houston for awhile getting these infusions, that’s not feasible for every family. But we’re hoping that she has a wonderful response and good news spreads about the trial and we’re optimistic.
Are you the only center involved in this trial?
Dr. Sandberg: Correct, yes.
Did I read that you’re doing a second trial as well and isn’t there one where it has never been injected?
Dr. Sandberg: The second trial is for a different disease called ependymoma and we’re infusing a drug which seems to have a great promise in the laboratory and we’re hopeful that we’ll see good responses for that drug as well.
Have you started patients in that one yet?
Dr. Sandberg: We have treated four patients so far in that trial and we just enrolled the fifth.
It’s too early to say results but safety wise things are looking good?
Dr. Sandberg: Yeah, safety wise it’s been absolutely fine and we’ve had a few patients who have had a decrease of some of their tumors and we’ve had some growth of tumors in some other patients and so we’ll have to see what happens over time. But certainly some of the results are promising.
Is this the drug that had never been injected before?
Dr. Sandberg: Correct, correct.
That’s for the ependymoma part of the study?
Dr. Sandberg: Correct.
Is it a completely new way of thinking with chemotherapy in general, not just with kids necessarily but to inject it directly into the tumor, into the brain?
Dr. Sandberg: There are a lot of scientists that have brilliant ideas about what should be the next drug, what is going to be the magic bullet that’s actually going to cure cancer, cure a specific cancer in children. My question for those scientists is that might be a wonderful idea but how are you going to get the drug where it needs to go in the brain. I’m a big believer in local drug delivery particularly for the brain. This is a new approach; we’re at the beginning of a journey and we don’t know what’s going to happen. We’ve had some exciting preliminary responses and we’ve had some failure too, but we’re trying something new because I think the current treatments that are available for children with these brain tumors are entirely inadequate.
Chemotherapy has been around a long time, do you think it should have evolved more by now? The way it’s delivered? Because it feels like it really hasn’t changed much.
Dr. Sandberg: I mean there have been trials of local drug delivery into the brain which have increased in frequency over the past decade or so. People pay less attention to these rare diseases in children. This isn’t as common as for example, glioblastoma multiforme which is a much more common malignant tumor in adults and there’s a lot more focus on that. In my opinion there aren’t enough people working on these tumors so I think the answer to your question is yes, there hasn’t been enough attention payed to these diseases and there hasn’t been enough attention payed to new approaches but that’s why we’re doing what we’re doing.
For these studies, what is the next step? Take me through the next couple of years with this.
Dr. Sandberg: We have two open clinical trials right now and the next step is we enroll patients and we honestly asses our results. What happens to these patients do they live or do they die, is their tumor less, is it smaller, what toxicity do they have? And we get together with the scientific community and we say, is this a good idea, what should we do next; it’s a step wise process. But I consider it an emergency because when you have a family who has a child who has cancer it’s an emergency because that child is fighting for their life so I’m really a big believer in pushing things along as quickly as possible.
Tell me a little bit about Sydney, how she is doing, how she has done so far with it?
Dr. Sandberg: First of all Sydney is the most remarkable young lady, she is an unbelievable young woman. She comes from Arkansas from a wonder family and she has the best personality. She’s hilarious she is always making us laugh. Sydney had a recurrent medulloblastoma and she came on our original trial where we were first infusing a very low dose of methotrexate into the forth ventricle of the brain. And she had two tumors in her brain and both of them got dramatically smaller. So we kept giving her more and more drug over the course of a year and she felt fine, she did beautifully during those infusions. And then she had a couple of years where she was doing well without recurrence. Then unfortunately as these tumors can her tumor came back in a separate area of the brain. So she had surgery in Arkansas and then radiation therapy and now her tumor has come back in the original place where we treated it so because she had such a successful response and three years is a long time for one of these tumors to stay away we’re trying to be even more progressive with a higher dose of the same drug that she was on before and adding a second drug infusing them into the ventricle. So far she’s done very well with the infusions.
Has her tumor shrunk?
Dr. Sandberg: We don’t know yet. What we do is give infusions over a six week period and then get an MRI scan at the end. So she’s towards the end of her fifth week, next week is her final week and she’s going to get two more infusions and then we’re going to pray for a good result on the MRI scan that follows.
So the MRI scan will happen in the next couple of weeks?
Dr. Sandberg: The MRI scan will happen within a week after the last infusion.
What could this mean for patients?
Dr. Sandberg: I’ve treated a lot of children with brain tumors over the course of my career, and they’re wonderful children from wonderful families and we share their pain when a child dies of that disease. And we share their pain when a child suffers disabilities not just because of the cancer that they have but because of the treatments right. I’ve seen so many kids have so many different problems and there are very few of them who lead absolutely normal lives. I hate the word normal because you know none of us are normal. But they have problems in school with learning and thinking, they have endocrine problems, they have motor problems, and sometimes that’s because of the tumor but sometimes that because of the treatments that they received. I’m looking for treatments that help them have a better quality of life. The first thing is always survival we want these kids to live. But we want them to live and have the best possible lives that they can.
The drugs that you’re giving directly into the brain, if you weren’t doing that, would they be getting just mega high doses of this same drug?
Dr. Sandberg: It depends; there are different protocols, some of which include some of these drugs that I’m mentioning. But we showed in animals that with a very small infusion you can get over eighty fold the drug level at the site where you need the drug level than if you give the same drug in the veins and that’s really remarkable.
Are you using that much less of the drug?
Dr. Sandberg: We’re using still a much lower dose than you would give if you give it systemically.
END OF INTERVIEW
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